Fondaparinux sodium (CAS 114870-03-0) is a member of oligosaccharides/heparins with a chemical name of O-[2-Deoxy-6-O-sulfo-2-(sulfoamino)-alpha-D-glucopyranosyl]-(1-4)-O-(beta-D-glucopyranurosonyl)-(1-4)-O-[2-deoxy-3,6-di-O-sulfo-2-(sulfoamino)-alpha-D-glucopyranosyl]-(1-4)-O-(2-O-sulfo-alpha-L-idopyranurosonyl)-(1-4)-O-[2-deoxy-1-O-methyl-6-O-sulfo-2-(sulfoamino)-alpha-D-glucopyranoside]decasodium salt, which developed by Choay, S. A. (see U.S. Pat. No. 4,818,816). The compound is a synthetic pentasaccharide Factor Xa inhibitor which is indicated as an anticoagulant drug used for the prevention of deep vein thrombosis in patients who have had orthopedic surgery as well as for the treatment of deep vein thrombosis and pulmonary embolism. It was approved by the United States Food and Drug Administration in 2001, marketed under the trade name Arixtra™ which is administrated subcutaneously.
The preparation process of Fondaparinux sodium disclosed in U.S. Pat. No. 4,818,816 is unsuitable for a large scale production since this process takes over 60 steps to afford a final product with low yield.
U.S. Pat. No. 8,288,515 applies protection and de-protection steps to prepare Fondaparinux sodium. However, the de-protection step results in low yields and consumes additional reaction time.
Another process is disclosed in U.S. 2011/0306757, but the additional reduction step of an azide needs further purification and the final N-sulfonation step remains in low yield (68%).
US 2012/0116066 describes the preparation of Fondaparinux sodium and its intermediates. However, the preparation of some intermediates such as EMod3 needs column purification. Moreover, the low α/β ratios in the coupling between C monomer and D monomer as well as numerous time-consuming procedures are not optimal.
In view of the above, there is still a need for a simple process with higher yield/purity for industrial preparation of Fondaparinux sodium.